Obesity results when the number of calories ingested exceed the number of calories expended. The ability of the body to match caloric intake to caloric expenditure depends on a number of cytokines. Leptin is a cytokine released directly from adipocytes in proportion to the amount of body fat and acts on a variety of CNS circuits to regulate food intake, energy expenditure and peripheral glucose regulation. This proposal focuses upon another cytokine that parallels at least some of these actions of leptin: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). Our data indicate that when GM-CSF is administered into the CNS, it produces reductions in food intake and body weight that cannot be attributed to illness or motor impairment. Further, GM-CSF receptors can be found in several key hypothalamic nuclei linked to the control of food intake including the arcuate nucleus, which also shows high expression of the leptin receptor. Finally, mice that do not make GM-CSF show increased food intake and body fat. These data point to an important role for GM-CSF in the control of energy balance and the aims of this proposal focus upon elucidating key aspects of GM-CSF's biological function. First, our data implicate central production of GM- CSF as contributing to the regulation of energy balance. Consequently, we want to do map GM-CSF receptor distribution and identify the neurochemicals made by neurons that express GM-CSF receptors. We also will identity the locations and cellular types that produce GM-CSF in the CNS. Second, both leptin and GM-CSF are cytokines with similar actions on food intake and energy balance. In this aim we will test the hypothesis that GM-CSF's actions on food intake and energy balance are produced by activating aspects of the leptin receptor intracellular signaling cascade. Third, our preliminary data indicates that despite their increased adipose stores, GM-CSF mice show evidence of lowered adipose-tissue inflammation. Consequently, we hypothesize a separate function for GM-CSF in adipose tissue to contribute to the inflammatory cascade that links obesity to insulin resistance. To test this hypothesis we will measure macrophage accumulation and expression of various cytokines in adipose tissue in GM-CSF deficient mice. The aims presented here are an important step in unveiling the specific roles that GM-CSF plays in the normal regulation of body weight and its potential connection to the pathology of diabetes.